Many HIV infected nursing mothers in the developing world are now receiving antiretrovirals (ARV's) for maintenance of their own health and in clinical trials for prevention of breast milk HIV transmission. While preliminary data demonstrate that all ARV's tested to date are present in breast milk, this data is inadequate to accurately determine infant drug dose from breast milk and infant drug exposure from that dose. These effects may be beneficial, such as protection of uninfected infants from infection by HIV in breast milk, or adverse, such as the development of ARV resistant viral strains in infected infants or drug toxicity from chronic ARV exposure. A quantitative understanding of infant breast milk ARV dose and drug exposure is required before ARV's can be used safely in nursing mothers as part of clinical care or research protocols. The ratio of breast milk to maternal plasma drug or serum concentrations is not constant, and extrapolation from determinations of this ratio at random time points is unreliable and may be misleading. More intensive sampling of nursing mothers and their infants is not practical in most environments. This project proposes a novel and innovative approach using sparse sampling and population pharmacokinetic modeling. Concentrations of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) will be measured in maternal plasma, breast milk and infant filter paper samples collected with a sparse sampling strategy. This data will be used to develop population models of ZDV, 3TC and NVP pharmacokinetics in maternal blood, breast milk and infant blood and to describe infant systemic ARV exposure from breast milk during maternal ZDV/3TC/NVP therapy. A pharmacokinetic approach involving population modeling has never before been used to describe breast milk drug transfer and exposure. The innovative approach proposed in this project can serve as a model for an efficient and practical way to study the extent and effects of transfer of all drugs in breast milk. This project will use a new analytic approach to describe transfer of antiretrovirals in breast milk from HIV infected mothers receiving antiretroviral therapy to their nursing infants. This information is needed for the safe and effective use of antiretrovirals in nursing women, and will pioneer a novel approach to the study of breast milk drug transfer.